cART has dramatically changed the phenotype of HIV-associated neurocognitive disease (HAND), but has neither eradicated it or decreased its prevalence. Thus we hypothesize there is a reversible metabolic component of HIV-1 associated neurologic disease with the molecular target of mixed lineage kinase type 3 (MLK3) that we can define in laboratory models, design rational adjunctive neuroprotective drugs for using our series of lead compounds URMC-099c*, then test in our in vitro and in vivo models of NeuroAIDS, with the goal of advancing the most efficacious development compound to the FDA for IND filing within this grant cycle. In the previous cycle, we validated MLK3 as an enzyme pathologically activated by HlV-1 neurotoxins, then successfully developed a small molecule MLK3 inhibitor, URMC-099 capable of achieving therapeutic concentrations in the CNS. For this competing renewal application, we have built on our experience with our industry partner to synthesize a series of small molecule MLK3 inhibitors with drug-like properties for testing in our models of HAND that investigate neuroinflammation and synaptodendritic damage. Thus, our administrative Core A will coordinate all projects and cores as follows: Project 1 will test novel URMC-099c* developed by our industry partner, Califia Bio, Inc (Project 2) to determine in vitro and in vivo endpoints of MLK3 inhibition in preventing neuroinflammation and synaptodendritic damage. Project 1 will use mathematical modeling and biostatistical expertise in Sub-Core A, supported by the URMC D-CFAR to formulate algorithms of efficacy for advancement of URMC-099c* in Projects 2 and 3. Project 2 will use a hypothesis-driven testing funnel with models developed in Project 1 to advance the synthesis of URMC-099c* to development compound (i.e. final drug formulation). Project 3 will test the most efficacious of URMC-099c* in a CD34 chronic murine model of HAND using novel in vivo neuroimaging (magnetic resonance spectroscopy, diffusion tensor imaging, SPECT) techniques to assess neuroprotection. Additionally, in the latter half of this program, Project 3 will test the efficacy of our development compound in a chronic monkey model of HAND with support by the UNMC P30 CHAIN Center. With the support of the URMC CTSI, Core A will then apply to the NIH Rapid Access for Interventional Development (RAID) program for good laboratory practice (GLP) scale-up and manufacture, as well as remaining safety and toxicity studies of our development compound, prior to filing an IND with the FDA. Our PPG as configured defines a paradigm for a bench-to-bedside path to adjunctive therapy based on MLK3 inhibition.